Decoding TCF1-controlled transcriptional program that promotes memory T cell fate

解码 TCF1 控制的转录程序，促进记忆 T 细胞的命运

• 批准号: 8650791
• 负责人: Hai-Hui Xue
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-10 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650791
• 关键词: Antigens; Bacteria; Bioinformatics; CD8B1 gene; Cell Maturation; Cell physiology; Cells; ChIP-seq; Clonal Expansion; Complex; Coupled; Data Set; Defect; Equilibrium; Family; Frequencies; Gene Expression Profile; Gene Proteins; Generations; Genes; Immunity; Immunologic Memory; Immunotherapy; Infection Control; Infectious Agent; Knockout Mice; Knowledge; Lead; Link; Maps; Massive Parallel Sequencing; Mediating; Memory; Molecular; Molecular Target; Pathway interactions; Phase; Play; Regulator Genes; Role; SELL gene; Signal Pathway; Signal Transduction; Staging; T cell response; T cell transcription factor 1; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Transcription Factor AP-1; Transcriptional Regulation; Vaccine Adjuvant; Vaccines; Virus; base; cancer cell; cell mediated immune response; chromatin immunoprecipitation; design; functional genomics; gene complementation; genome-wide; improved; interest; novel; novel strategies; pathogen; programs; public health relevance; self-renewal; transcription factor; transcriptomics

DESCRIPTION (provided by applicant): CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. CD8 T cell-mediated immune responses consist of several distinct stages, including activation of antigen-specific na¿ve CD8 T cells, clonal expansion of effector CD8 T cells, and formation of memory CD8 T cells. Among effector CD8 T cells, the KLRG1+IL-7R¿- cells are considered to be terminally differentiated cytolytic effectors, and KLRG1loIL-7R¿+ cells have increased potential to give rise to long-lasting memory CD8 T cells and deemed to be memory precursors. Among memory CD8 T cells, CD62L+ central memory T cells are more efficient in homestatic self-renewal and secondary proliferation than CD62L- effector memory T cells. The T cell factor 1 (TCF1) transcription factor is known to mediate the canonical Wnt signaling and play important roles in T cell development. In recent years, studies by us and others discovered its emerging roles in regulating mature CD8 T cell responses. Specifically, activation of the Wnt signaling pathway in CD8 T cells was sufficient to expand the memory CD8 T cell pool. Furthermore, among all the transcription factors that have been studied in CD8 T cell responses to date, TCF1 deficiency most profoundly impaired central memory T cell maturation, memory T cell persistence and secondary expansion. Our preliminary studies further revealed that albeit TCF1 was significantly downregulated in KLRG1+IL-7R¿- effector T cells, substantial expression of TCF1 was retained in KLRG1loIL-7R¿+ memory precursors and CD62L+ central memory cells. In addition, loss of TCF1 greatly diminished the frequency of memory precursors at the effector phase. Based on these findings, we hypothesize that TCF1 controls unique transcriptional programs during CD8 T cell responses and retention of TCF1 and its downstream genes in CD8 effectors favors differentiation of memory precursors and formation of self-renewing central memory T cells. We propose to test this hypothesis through the following specific aims: Specific Aim 1. To elucidate the TCF1-regulated gene regulatory circuits throughout the CD8 T cell responses. Specific Aim 2. To identify TCF1 downstream genes that promote generation of memory precursors and central memory T cells. Through these proposed studies, what we will achieve is to elucidate the molecular wiring of TCF1-controlled gene regulatory program and determine its functional importance in promoting generation of robust and long- lasting memory CD8 T cells. These systematic approaches may lead to discovery of key determinants directing CD8 effectors to a memory fate. This project will have a major impact on devising strategies to utilize Wnt- derived signals or their molecular targets to improve vaccine/adjuvant design, aiming for enhanced T cell immunity against infectious agents and malignant cells.

描述（由适用提供）：CD8 T细胞对于控制包括病毒和细胞内细菌在内的细胞内病原体感染至关重要。 CD8 T细胞介导的免疫调查会由几个不同的阶段组成，包括激活抗原特异性NA¿VECD8 T细胞，效应CD8 T细胞的克隆膨胀以及记忆CD8 T细胞的形成。在效应的CD8 T细胞中，KLRG1 + IL-7R®-细胞被认为是终末分化的胞溶作用，而KLRG1LOIL-7R？ +细胞具有增加可能引起持久记忆CD8 T细胞的潜力，并被认为是记忆前体。在存储器CD8 T细胞中，CD62L+中央记忆T细胞在寄宿自我更新和次要增殖中比CD62L效应记忆T细胞更有效。已知T细胞因子1（TCF1）转录因子介导规范的Wnt信号传导并在T细胞发育中起重要作用。近年来，我们和其他人的研究发现了其在确定成熟CD8 T细胞反应中的新作用。具体而言，CD8 T细胞中Wnt信号通路的激活足以扩展内存CD8 T细胞池。此外，在迄今为止在CD8 T细胞反应中研究的所有转录因子中，TCF1缺乏症最严重受损的中央记忆T细胞成熟，记忆T细胞持久性和二次扩张。我们的初步研究进一步表明，尽管TCF1在KLRG1+ IL-7R®-效应T细胞中显着下调，但在KLRG1LOIL-7R+存储前体和CD62L+中心记忆细胞中保留了TCF1的大量表达。此外，TCF1的丢失大大降低了效应器阶段内存前体的频率。基于这些发现，我们假设TCF1控制CD8 T细胞反应期间独特的转录程序，并保留TCF1及其在CD8中的下游基因效应效应的下游基因有利于记忆前体的差异和形成自我更新中心记忆T细胞。我们建议通过以下特定目的检验这一假设：特定目的1。阐明整个CD8 T细胞反应中TCF1调节的基因调节回路。具体目标2。确定促进记忆前体和中央记忆T细胞产生的下游基因。通过这些提出的研究，我们将实现的目的是阐明TCF1控制的基因调节程序的分子布线，并确定其在促进稳健和持久记忆CD8 T细胞产生的功能重要性。这些系统的方法可能会导致发现关键的决定者将CD8效应引向记忆命运。该项目将对制定策略采用WNT衍生信号或其分子靶标有重大影响，以改善疫苗/辅助设计，旨在增强针对感染剂和恶性细胞的T细胞免疫学。